Studies on naloxone have shown enhanced brain concentrations of naloxone in single dose morphine pretreated or morphine pellet implanted mice. This enhancement has been found for etorphine as well. In cross tolerance studies morphine pellet implanted mice were tolerant to morphine s.c. but were not cross tolerant to etorphine. If the morphine pellet was removed (3 hrs), the mice were tolerant to both morphine and etorphine. These studies involved analgesic ED50's and will be extended to lethality and antidiuretic effects. A goal is to see whether the phenomenon occurs to other narcotics such as heroin and methadone. It seems to occur for heroin. Since classically cross tolerance studies have been done under what we think are partial withdrawal conditions, our results are not iconoclastic but in fact should lead to a better understanding of complexities of tolerance and withdrawal. The mechanism proposed involves studies on the changes in permeability of the blood brain barrier. The initial implication is based on observations that intracerebroventricular administration of the challenging narcotic agents produced no differential potency. Therefore, the blood brain barrier changes in permeability to certain narcotics and not others as tolerance develops. The specificity of the effect depends upon the permeability characteristics of lipophilicity and potency of the narcotic.